This invention relates to phenyl urea and phenyl thiourea derivatives and their use as pharmaceuticals
It is well established that many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers, e.g. cAMP (Letkowitz, Nature, 1991, 351:353-354). Examples of these proteins include the GPC receptors, such as those for adrenergic agents and dopamine (Kobilka B. K. et al, Proc. Natl Acad Sci., USA, 1987, 84:46-50; Kobila B. K. et at, Science, 1987, 238:650-656; Bunzow, J. R. et al, Nature, 1988, 336:783-787), G-proteins themselves, effector proteins, e.g. phospholipase C, adenyl cyclase, and phosphodiesterase, and actator proteins, e.g. protein kinase A and protein kinase C (Simon, M. I. et al, Science, 1991, 252:802-8).
The membrane protein gene superfamily of G-protein coupled receptors has been characterised as having seven putative transmembrane domains. The domains are believed to represent transmembrane xcex1-helices connected by extracellular or cytoplasmic loops. G-protein coupled receptors include a wide range of biologically active receptors, such as hormone, viral, growth factor and neuro-receptors.
G-protein coupled receptors have been characterised as including these seven conserved hydrophobic stretches of about 20 to 30 amino acids, connecting six divergent hydrophilic loops. The G-protein family of coupled receptors includes dopamine receptors which bind to neuroleptic drugs used for treating psychotic and neurological disorders. Other examples of members of this family include, but are not limited to, calcitonin, adrenergic, endothelin, cAMP, adenosine, muscarinic, acetylcholine, serotonin, histamine, thrombin, kinin, follicle stimulating hormone, opsins, endothelial differentiation gene-1, rhodopsins, odorant, and cytomegalovirus receptors.
Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, HFGAN72, have been identified and are disclosed in U.S. Ser. Nos. 08/846,704 and 08/846,705, both of which were filed on Apr. 30, 1997, as well as in WO 96/34877.
Polypeptides and polynucleotides encoding polypeptides which are ligands for the HFGAN72 receptor are disclosed in U.S. Ser. No. 08/939,093 filed Jul. 2, 1997, U.S. Ser. No. 08/820,519 filed Mar. 19, 1997 and U.S. Ser. No. 08/033,604 filed Dec. 17, 1996.
HFGAN72 receptors are found in the mammalian host and, thus, may be responsible for many biological functions, including many pathologies including, but not limited to, depression; anxiety; obsessive compulsive disorder, affective neurosis/disorder; depressive neurosis/disorder, anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington""s disease and Gilles de la Tourett""s syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; asthma; cancer; Parkinson""s disease; Cushing""s syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; Froehlich""s syndrome; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman""s syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome, heart and lung diseases, mental illness such as depression or schizophrenia, and addictions; acute and congestive heart failue; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and other neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.
Experiments have shown that central administration of Lig 72A for the HFGAN72 receptor (Lig 72A is described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that Lig 72A may be an endogenous regulator of appetite. Therefore, antagonists of its receptor may be useful in the treatment of obesity and diabetes, see Cell, 1998, 92, 573-585.
There is a significant incidence of obesity in westernised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a furter 22% clinically obese. It has been estimated that 5.7% of all healthcare costs in the USA are a consequence of obesity. About 85% of Type 2 diabetics are obese, and diet and exercise are of value in all diabetics. The incidence of diagnosed diabetes in westernised countries is typically 5% and there are estimated to be an equal number undiagnosed. The incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects. Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaemia, whilst metformin causes GI side-effects. No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.
Rat sleep/EEG studies have also shown that central administration of LIG72A, an agonist of HFGAN72 receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia
The present invention provides phenyl urea and phenyl thiourea derivatives which are non-peptide antagonists of the human HFGAN72 receptor. In particular, these compounds are of potential use in the treatment of obesity including obesity observed in Type 2 (non-insulin-dependent) diabetes patients and/or sleep disorders.
Several phenyl urea derivatives are known in the literature, viz:
WO 93/18028 discloses the compound N-1-isoquinolinyl-Nxe2x80x2-(1-methyl-1H-indol-5-yl)urea;
DE 2928485 discloses the compounds N-(3-chloro-4-trifluoromethylphenyl)-Nxe2x80x2-4-quinolinylurea, and N-(3-chloro-4-trifluoromethylphenyl)-Nxe2x80x2-(5-nitro-4-quinolinyl)urea;
DE 2801187 discloses the compound N-(3,4,5-trimethoxyphenyl)-Nxe2x80x2-(7-chloro-4-quinolinyl)urea; and
U.S. Pat. No. 3,406,176 discloses the compounds N-(4-methoxyphenyl)-Nxe2x80x2-(7-chloro-4-quinolinyl)urea, and N-(4-chlorophenyl)-Nxe2x80x2-(7-chloro-4-quinolinyl)urea;
none of these documents suggest the use of phenyl urea derivatives as HFGAN72 receptor antagonists.
According to the present invention there is provided a compound of formula (I): 
in which:
X and Y independently represent CH or nitrogen, provided that X and Y do not both represent CH;
Z represents oxygen or sulphur,
R1 represents (C1-6)alkyl, (C2-6)alkenyl or (C1-6)alkoxy, any of which may be optionally substituted; halogen, R7COxe2x80x94 or NR8R9COxe2x80x94;
R2, R3, R4, R5 and R6 independently represent (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy or (C1-6)alkylthio, any of which may be optionally substituted; hydrogen, halogen, nitro, cyano, aryloxy, aryl(C1-6)alkyloxy, aryl(C1-6)alkyl, R7COxe2x80x94, R7SO2NHxe2x80x94, R7CON(R10)xe2x80x94, NR8R9xe2x80x94, NR8R9COxe2x80x94, xe2x80x94COOR8 or heterocyclyl; provided that at least one of R2, R3, R4, R5 and R6 is other than hydrogen;
or an adjacent pair of R2, R3, R4, R5 and R6 together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring;
R7 is (C1-6)alkyl or aryl;
R8 and R9 independently represent hydrogen, (C1-6)alkyl, aryl or aryl(C1-6)alyl;
R10 is hydrogen or (C1-6)alkyl; and
n is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof;
provided that the compound is not:
a) N-1-isoquinolinyl-Nxe2x80x2-(1-methyl-1H-indol-5-yl)urea;
b) N-(3-chloro-4-trifuoromethylphenyl)-Nxe2x80x2-4-quinolinylurea;
c) N-(3-chloro-4-trifluoromethylphenyl)-Nxe2x80x2-(5-nitro-4-quinolinyl)urea;
d) N-(3,4,5-trimethoxyphenyl)-Nxe2x80x2-(7-chloro-4-quinolinyl)urea;
e) N-(4-methoxyphenyl)-Nxe2x80x2-(7-chloro-4-quinolinyl)urea; or
f) N-(4-chlorophenyl)-Nxe2x80x2-(7-chloro-4-quinolinyl)urea
In formula (I) X preferably represents CH, Y preferably represents nitrogen and Z preferably represents oxygen.
When a halogen atom is present in the compound of formula (I) this may be fluorine, chlorine, bromine or iodine.
n is preferably 0 or 1.
When Y is nitrogen and n is 1, the group R1 is preferably in the 6- or 8-position, particularly the 6-position.
R1 is preferably halogen e.g. fluoro, or (C1-6)alkoxy e.g. methoxy. R1 is most preferably fluoro.
When any one of R1 to R6 comprise a (C1-6)alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkylthio, the alkyl group may be straight chain or branched, it preferably contains 1 to 4 carbon atoms and is most preferably methyl or ethyl.
When any one of R1 to R6 comprise a (C2-6)alkenyl group, whether alone or forming part of a larger group, the alkenyl group may be straight chain or branched, it preferably contains 2 to 4 carbon atoms and is most preferably allyl.
Suitable optional substituents for (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxy and (C1-6)alkylthio groups include one or more substituents selected from halogen e.g. fluoro, (C1-4)alkoxy e.g. methoxy, hydroxy, carboxy and (C1-6)alkyl esters thereof, amino, mono- or di-(C1-6)alkylamino and cyano.
When used herein the term xe2x80x9carylxe2x80x9d, whether alone or forming part of a larger group, includes optionally substituted aryl groups such as phenyl and naphthyl, preferably phenyl. The aryl group may contain up to 5, more preferably 1, 2 or 3 optional substituents. Examples of suitable substituents for aryl groups include halogen, (C1-4)alkyl e.g. methyl, (C1-4)haloalkyl e.g. trifluoromethyl, (C1-4)alkoxy e.g. methoxy, (C1-4)alkoxy(C1-4)alkyl e.g. methoxymethyl, hydroxy, carboxy and (C1-6)alkyl esters thereof, amino, nitro, arylsulphonyl e.g. p-toluenesulphonyl, and C1-4 alkylsulphonyl e.g. methanesulphonyl.
When any one of R2 to R6 represent heterocyclyl, this group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated or unsaturated, for example containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur; for example pyrrolidine, oxazole, morpholine, pyrimidine or phthalimide. A ring containing one or two nitrogen atoms is especially preferred. The heterocyclyl group may contain up to 5, more preferably 1, 2 or 3 optional substituents. Examples of suitable substituents for heterocyclyl groups include halogen, (C1-4)alkyl e.g. methyl, (C1-4)haloalkyl e.g. trifluoromethyl, (C1-4)alkoxy e.g. methoxy, (C1-4)alkoxy(C1-4)alkyl e.g. methoxymethyl, hydroxy, carboxy, amino, nitro, arylsulphonyl e.g. p-toluenesulphonyl, and (C1-4)alkylsulphonyl e.g. methanesulphonyl.
When an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring it is preferably a 5- to 7-membered ring, which may be aromatic or non-aromatic. Heterocyclic rings preferably contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur; for example oxazole, imidazole, thiophene, pyran, dioxan, pyrrole or pyrrolidine. A ring containing one nitrogen atom and one oxygen atom is preferred. It is particularly preferred for the nitrogen to be attached directly to the R4 position. A carbocyclic or heterocyclic ring formed by an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached may be optionally substituted on carbon or nitrogen by one or more substituents, e.g. up to 3 substituents. Examples of suitable substituents for the carbocyclic or heterocyclic ring include xe2x95x90O, (C1-4)alkyl e.g. methyl, aryl(C1-4)alkyl e.g. benzyl or 3-phenylpropyl, aryl e.g. phenyl, (C1-4)alkoxy, (C1-4)alkoxy(C1-4)alkyl e.g. methoxymethyl, hydroxy, hydroxy(C1-4)alkyl e.g. hydroxyethyl, RaCO2xe2x80x94, RaCO2(C1-4)alkyl e.g. carboethoxypropyl, cyano, cyano(C1-4)alkyl e.g. 3-cyanopropyl, RaRbN and RaRbN(C1-4)alkyl; in which Ra and Rb are independently selected from hydrogen and (C1-4)alkyl.
A preferred group of compounds are those in which R2 to R6 independently represent hydrogen, halogen, (C1-6)alkoxy e.g. methoxy, (C1-6)alkylthio e.g. methylthio, or NR8R9 wherein R8 and R9 preferably represent (C1-6)alkyl e.g. dimethylamino, and at least one of R2 to R6 is other than hydrogen; or an adjacent pair of R2 to R6 together with the carbon atoms to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring, e.g. a 6 or 7-membered non-aromatic heterocyclic ring or a 5- or 6-membered aromatic heterocyclic ring.
A further preferred group of compounds are those in which R2, R5 and R6 represent hydrogen.
A further preferred group of compounds are those in which R2, R4 and R6 represent hydrogen.
A preferred group of compounds are those in which either R3 and R4, or R3 and R5 are other than hydrogen.
A group of compounds according to the invention which may be mentioned are the compounds of formula (Ia): 
in which:
X and Y independently represent CH or nitrogen, provided that X and Y do not both represent CH;
Z represents oxygen or sulphur,
R1 represents halogen or (C1-6)alkoxy;
R3 and R4 independently represent hydrogen, halogen, nitro, cyano, (C1-6)alkyl, (C1-6)alkoxy, aryloxy, CF3O, (C1-6)alkylthio, amino, mono- or di-(C1-6)alkylamino, monoarylamino, mono(C1-6)alkylarylarnino, R7COxe2x80x94, R7SO2NHxe2x80x94, R7CON(R10)xe2x80x94, NR8R9COxe2x80x94 or heterocyclyl;
or R3 and R4 together with the carbon atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring;
R7 is (C1-6)alkyl or aryl;
R8 and R9 independently represent hydrogen, (C1-6)alkyl, aryl or (C1-6)alkylaryl;
R10 is hydrogen or (C1-6)alkyl; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
Another group of compounds according to the invention which may be mentioned are the compounds of formula (Ib): 
in which:
X and Y independently represent CH or nitrogen, provided that X and Y do not both represent CH;
Z represents oxygen or sulphur;
R1 represents halogen or (C1-6)alkoxy;
R3 and R4 independently halogen or (C1-3)alkoxy or together with the carbon atoms to which they are attached form an optionally substituted heterocyclic ring; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts.
It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulphonic, methanesulphonic or naphthalenesulphonic acid. Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).
The invention extends to all isomeric forms including stereoisomers and geometric isomers of the compounds of formula (I) including enantiomers and mixtures thereof e.g. racemates. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
According to a further feature of the invention we provide a process for the preparation of the compounds of formula (I) and salts thereof which comprises coupling a compound of formula (II); 
with a compound of formula (III); 
wherein A and B are appropriate functional groups to form the xe2x80x94NHCONHxe2x80x94 or xe2x80x94NHCSNHxe2x80x94 moiety when coupled; X, Y and n are as defined in formula (I); and R1xe2x80x2 to R6xe2x80x2 are R1 to R6 as defined in formula (I) or groups convertible thereto; and thereafter optionally and as necessary and in any appropriate order, converting any R1xe2x80x2 to R6xe2x80x2 when other than R1 to R6 respectively to R1 to R6, and/or forming a pharmaceutically acceptable salt thereof.
Suitable examples of groups A and B are:
(i) A is xe2x80x94CON3 and B is xe2x80x94NH2 
(ii) A is xe2x80x94NH2 and B is xe2x80x94NH2 
(iii) A is xe2x80x94CO2H and B is xe2x80x94NH2 
(iv) A is xe2x80x94Nxe2x95x90Cxe2x95x90O and B is xe2x80x94NH2 
(v) A is xe2x80x94NH2 and B is xe2x80x94Nxe2x95x90Cxe2x95x90O
(vi) A is xe2x80x94Nxe2x95x90Cxe2x95x90S and B is xe2x80x94NH2 
(vii) A is xe2x80x94NH2 and B is xe2x80x94Nxe2x95x90Cxe2x95x90S
(viii) A is xe2x80x94NHCOL and B is xe2x80x94NH2 
(ix) A is xe2x80x94NH2 and B is xe2x80x94NHCOL
(x) A is halogen and B is xe2x80x94NHCONH2.
Wherein L is a leaving group such as chloro or bromo, imidazole or phenoxy or phenylthio optionally substituted for example with halogen, for example chlorine.
When A and B are both NH2, the reaction is generally effected in the presence of a urea coupling agent such as carbonyldiimidazole.
When A is xe2x80x94CO2H and B is xe2x80x94NH2 the reaction is generally effected in the presence of an agent such as diphenylphosphoryl azide and in the presence of a base such as triethylamine.
When A is xe2x80x94NH2, xe2x80x94Nxe2x95x90Cxe2x95x90O or xe2x80x94Nxe2x95x90Cxe2x95x90S and B is xe2x80x94NH2, or when A is xe2x80x94NH2 and B is xe2x80x94Nxe2x95x90Cxe2x95x90O or xe2x80x94Nxe2x95x90Cxe2x95x90S the reaction is suitably carried out in an inert solvent for example dimethylformamide or dichloromethane and/or toluene at ambient or elevated temperature, preferably ambient.
When A is xe2x80x94CON3 or xe2x80x94CO2H and B is xe2x80x94NH2 the reaction is suitably carried out in an inert solvent for example toluene or dimethylformamide at elevated temperature.
Where A is xe2x80x94NHCOL and B is xe2x80x94NH2 or when A is xe2x80x94NH2 and B is xe2x80x94NHCOL, the reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in dimethylformamide at ambient or elevated temperature.
When A is halogen and B is xe2x80x94NHCONH2 the reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of base.
Suitable examples of compounds having groups R1xe2x80x2 to R6xe2x80x2 which are convertible to R1 to R6 respectively include compounds where an adjacent pair of R2xe2x80x2 to R6xe2x80x2 together with the carbon atoms to which they are attached represent a fused pyrrole ring which is unsubstituted on nitrogen, where treatment with a base, e.g. sodium hydride, and reaction with an electrophile, e.g. methyl iodide, benzyl chloride or benzenesulfonyl chloride, affords the corresponding substituent on the pyrrole nitrogen.
Compounds of formula (II) where A is xe2x80x94NH2 are known compounds or can be prepared analogously to known compounds.
Compounds of formula (II) where A is xe2x80x94Nxe2x95x90Cxe2x95x90O may be prepared by treating a compound of formula (II) in which:
(i) A is amino, with phosgene or a phosgene equivalent, in the presence of excess base or an inert solvent.
(ii) A is acylazide (i.e. xe2x80x94CON3), via the nitrene, by thermal rearrangement using conventional conditions (ref. L. S. Trifonov et al, Helv. Chim. Acta, 1987, 70, 262).
(iii) A is xe2x80x94CONH2, via the nitrene intermediate using conventional conditions.
Compounds of formula (II) where A is xe2x80x94Nxe2x95x90Cxe2x95x90S are known compounds or can be prepared analogously to known compounds.
Compounds of formula (II) where A is xe2x80x94NHCOL may be prepared by reacting a compound of formula (II) in which A is xe2x80x94NH2 with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of a base such as triethylamine.
Compounds of formula (II) in which A is halogen are known compounds or can be prepared analogously to known compounds.
Compounds of formula (III) where B is xe2x80x94NH2 are known compounds or can be prepared analogously to known compounds.
Compounds of formula (III) where B is xe2x80x94Nxe2x95x90Cxe2x95x90O may be prepared by treating a compound of formula (III) in which:
(i) B is amino, with phosgene or a phosgene equivalent, in the presence of excess base or an inert solvent.
(ii) B is acylazide (i.e. xe2x80x94CON3), via the nitrene, by thermal rearrangement using conventional conditions (ref. L. S. Trifonov et al, Helv. Chim. Acta, 1987, 70, 262).
(iii) B is xe2x80x94CONH2, via the nitrene intermediate using conventional conditions.
Compounds of formula (UT) where B is xe2x80x94Nxe2x95x90Cxe2x95x90S are known compounds or can be prepared analogously to known compounds.
Compounds of formula (III) where B is xe2x80x94NHCOL may be prepared by reacting a compound of formula (III) in which B is xe2x80x94NH2 with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of a base such as triethylamine. Examples of phosgene equivalents include triphosgene, carbonyldiimidazole, phenyl chloroformate and phenyl chlorothioformate.
Compounds of formula (III) where B is xe2x80x94NHCONH2 can be prepared from the corresponding precursor where B is xe2x80x94NH2 by reaction with an isocyanate under conventional conditions.
The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds of formula (I). Libraries of compounds of formula (I) may be prepared by a combinatorial xe2x80x98split and mixxe2x80x99 approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I) or pharmaceutically acceptable salts thereof.
Novel intermediates of formulae (II) and (III) are also part of this invention.
According to a further feature of the invention we provide a compound of formula (II): 
wherein A is xe2x80x94CON3, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94Nxe2x95x90Cxe2x95x90O, xe2x80x94Nxe2x95x90Cxe2x95x90S, xe2x80x94NHCOL or halogen, L is a leaving group, X and Y are as defined in formula (I), n is 1, 2, 3 or 4, and R1xe2x80x2 is R1 as defined in formula (I) or a group convertible thereto.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
As indicated above the compounds of formula (I) and their pharmaceutically acceptable salts, including those compounds where X and Y both represent CH, and without provisos a)-f), are useful for the treatment of diseases or disorders where an antagonist of the human HFGAN72 receptor is required especially feeding disorders, such as obesity and diabetes; prolactinoma; hypoprolactinemia, hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; Cushings syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases, mental illness such as depression or schizophrenia, and addictions; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; bulimia; and hypopituitarism.
The compounds of formula (I) and their pharmaceutically acceptable salts, including those compounds in which X and Y both represent CH, and without provisos a)-f), are particularly useful for the treatment of obesity, including obesity associated with Type 2 diabetes, and sleep disorders.
Other diseases or disorders which may be treated in accordance with the invention include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; adrenohypophysis hypofunction; functional or psychogenic amenorrhea; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-polio syndrome and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics.
The present invention also provides a method of treating or preventing diseases or disorders where an antagonist of the human HFGAN72 receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, without the proviso that X and Y do not both represent CH and without provisos a)-f).
The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, without the proviso that X and Y do not both represent CH and without provisos a)-f), for use in the treatment or prophylaxis of disease or disorders where an antagonist of the human HFGAN72 receptor is required.
The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, without the proviso that X and Y do not both represent CH and without provisos a)-f), in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of the human HFGAN72 receptor is required.
For use in medicine, the compounds of the present invention are usually administered as a pharmaceutical composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The compounds of formula (I) and their pharmaceutically acceptable salts, including those compounds in which X and Y both represent CH and without provisos a)-f), may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
The compounds of formula (I) and their pharmaceutically acceptable salts, including those compounds in which X and Y both represent CH and without provisos a)-f), which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and patches.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.
The dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, including those compounds in which X and Y both represent CH and without provisos a)-f), used in the treatment or prophylaxis of the abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors. However as a general rule suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; such unit doses may be administered more than once a day for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months. In the case of physiologically acceptable salts the above figures are calculated as the parent compound of formula (I), including those compounds in which X and Y both represent CH and without provisos a)-f).
No toxicological effects are indicated/expected when a compound of formula (I), including those compounds in which X and Y both represent CH and without provisos a)-f), is administered in the above mentioned dosage range.
The human HFGAN72 receptor ligand 72A referred to above has the amino acid sequence:
The HFGAN72 receptor ligand referred to above can be employed in a process for screening for compounds (antagonists) which inhibit the ligand""s activation of the HFGAN72 receptor.
In general, such screening procedures involve providing appropriate cells which express the HFGAN72 receptor on the surface thereof. Such cells include cells from mammals, yeast, Drosophila or E. coli. In particular, a polynucleotide encoding the HFGAN72 receptor is employed to transfect cells to thereby express the receptor. The expressed receptor is then contacted with a test compound and an HFGAN72 receptor ligand to observe inhibition of a functional response.
One such screening procedure involves the use of melanophores which are transfected to express the HFGAN72 receptor. Such a screening technique is described in WO 92/01810.
Another such screening technique involves introducing RNA encoding the HFGAN72 receptor into Xenopus oocytes to transiently express the receptor. The receptor oocytes may then be contacted with a receptor ligand and a compound to be screened, followed by detection of inhibition of a signal in the case of screening for compounds which are thought to inhibit activation of the receptor by the ligand.
Another method involves screening for compounds which inhibit activation of the receptor by determining inhibition of binding of a labelled HFGAN72 receptor ligand to cells which have the receptor on the surface thereof. Such a method involves transfecting a eukaryotic cell with DNA encoding the HFGAN72 receptor such that the cell expresses the receptor on its surface and contacting the cell or cell membrane preparation with a compound in the presence of a labelled form of an HFGAN72 receptor ligand. The ligand can be labelled, e.g. by radioactivity. The amount of labelled ligand bound to the receptors is measured, e.g. by measuring radioactivity of the receptors. If the compound binds to the receptor as determined by a reduction of labelled ligand which binds to the receptors, the binding of labelled ligand to the receptor is inhibited.
Yet another screening technique involves the use of FLIPR equipment for high throughput screening of test compounds that inhibit mobilisation of intracellular calcium ions, or other ions, by affecting the interaction of an HFGAN72 receptor ligand with the HFGAN72 receptor. The ligand used in the screening method described below to determine the antagonist activity of compounds according to the invention is Lig 72A which has the amino acid sequence shown above.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.